Manoalide and its derivatives have been found to be useful in the treatments of cutaneous hyperproliferative dermatoses. Manoalide, when applied topically or systemically can inhibit ornithine decarboxylase (ODC), an important rate limiting enzyme in cellular growth. When skin cells, keratinocytes, are incubated with manoalide in vitro, there is a dose dependent inhibition of DNA synthesis. More particularly, application of manoalide is of therapeutic benefit in dermatoses involving benign or malignant hyperplasia such as psoriasis or skin cancers.
Ornithine decarboxylase (ODC) is a key regulatory enzyme in normal and neoplastic growth (D. H. Russell, Drug Metabol. Reviews 16, 1-88, 1985). ODC converts ornithine to putrescine and is the initial and rate limiting enzyme in the polyamine biosynthetic pathway. Polyamines (putrescine, spermidine, spermine) are the organic cations of the cell and accumulate in tissues in response to a growth stimulus (D. H. Russel and P. J. Stanbrook, Proc. Natl. Acad. Sci. USA 72, 1482, 1975; D. H. Russell and C. C. Levey, Cancer Res 31, 248, 1971; D. H. Russell and T. A. McVickers, Biochem Biophys. Acta, 259, 247, 1972). It has been amply demonstrated that ODC activity is elevated in proliferating cells and is induced in the epidermis by trophic hormones, mitogens, carcinogens and tumor promoters such as 12-O-tetra-decanoylphorbol-13-acetate (TPA).
The hallmark of many skin diseases is epidermal hyperproliferation. Psoriasis, for example is a hereditary skin disease. Persons with psoriasis develop skin lesions, either spontaneously or at sites of cutaneous damage, which show seemingly uncontrolled non-malignant growth of the epidermis. It is thought that this increased epidermal cell proliferation is an essential component of the pathophysiology of psoriasis. Russell et al. (J. Invest. Dermatol. 71, 177, 1977) has shown that ODC in psoriatic lesions was approximately six fold higher than in uninvolved skin. Elevations in putrescine, spermidine and spermine were also observed.
It has now been found that manolide and its analogs have the capacity to effectively modify epidermal ODC and thereby affect such diseases as psoriasis and neoplasias affected by modification of ODC activity.